NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression
NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression
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NFATc4 在 miR-133a 介导的心肌细胞肥大抑制中受到负调控
DOI：
10.1152/ajpheart.00592.2009
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发表时间：
2010-05-01
影响因子：
4.8
通讯作者：
Chang, Jiang
中科院分区：
文献类型：
--
作者：
Li, Qi;Lin, Xi;Chang, Jiang
Li Q，Lin X，Yang X，Chang J. NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression. Am J Physiol Heart Circ Physiol 298：H1340-H1347，2010.首次发表于2010年2月19日; doi：10.1152/ajpheart.00592.2009。NFAT（活化T细胞核因子）介导的肥大信号的活化是对肥大刺激的主要调节反应。最近的一项研究揭示了microRNA-133 a（miR-133 a）在心脏肥大中的潜在调节作用。然而，迄今为止，miR-133 a和NFAT信号之间没有联系。在这项研究中，我们确定了NFATc 4，一种肥大相关的介质，由miR-133 a负调控。验证了NFATc 4 3 '-非翻译区（UTR）和miR-133 a之间的两个保守碱基配对位点。NFATc 4 3 '-UTR中这些位点的突变完全阻断了miR-133 a对NFATc 4的负面作用，表明NFATc 4是miR-133 a调控的直接靶点。使用功能获得性方法，我们证明miR-133显著降低了内源性水平，以及肥大刺激介导的NFATc 4基因表达增加。miR-133 a对NFATc 4基因表达的后一种作用与α-肾上腺素能受体激动剂诱导的心肌细胞肥大减弱一致。相反，用miR-133 a抑制剂处理的细胞导致NFATc 4表达水平增加。miR-133 a的应用对NFATc 4核定位没有明显影响。我们的结论是NFATc 4表达的负调控有助于miR-133 a介导的肥大抑制。
Li Q, Lin X, Yang X, Chang J. NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression. Am J Physiol Heart Circ Physiol 298: H1340-H1347, 2010. First published February 19, 2010; doi:10.1152/ajpheart.00592.2009.-Activation of NFAT (nuclear factor of activated T cells)-mediated hypertrophic signaling is a major regulatory response to hypertrophic stimuli. A recent study unveiled potential regulatory roles for microRNA-133a (miR-133a) in cardiac hypertrophy. To date, however, no connection has been made between miR-133a and NFAT signaling. In this study, we determined that NFATc4, a hypertrophy-associated mediator, is negatively regulated by miR-133a. Two conserved base-pairing sites between the NFATc4 3'-untranslated region (UTR) and miR-133a were verified. Mutation of these sites in the NFATc4 3'-UTR completely blocked the negative effect of miR-133a on NFATc4, suggesting that NFATc4 is a direct target for miR-133a regulation. Using a gain-of-function approach, we demonstrate that miR-133 significantly reduces the endogenous level of, as well as the hypertrophic stimulus-mediated increase in, NFATc4 gene expression. This latter effect of miR-133a on NFATc4 gene expression was coincided with an attenuated cardiomyocyte hypertrophy induced by an alpha-adrenergic receptor agonist. Conversely, cells treated with miR-133a inhibitor resulted in an increase in NFATc4 expression level. Application of miR-133a had no apparent effect on NFATc4 nuclear localization. We conclude that the negative regulation of NFATc4 expression contributes to miR-133a-mediated hypertrophic repression.